Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, Observational, and Non-Randomized Open Label Interventional Study

Avner Ehrlich; Konstantinos Ioannidis; Makram Nasar; Ismaeel Abu Alkian; Yuval Daskal; Nofar Atari; Limor Kliker; Nir Rainy; Matan Hofree; Sigal Shafran Tikva; Inbal Houri; Arrigo Cicero; Chiara Pavanello; Cesare R. Sirtori; Jordana B. Cohen; Julio A. Chirinos; Lisa Deutsch; Merav Cohen; Amichai Gottlieb; Adina Bar-Chaim; Oren Shibolet; Michal Mandelboim; Shlomo L. Maayan; Yaakov Nahmias

doi:10.7554/eLife.79946

Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, Observational, and Non-Randomized Open Label Interventional Study

Avner Ehrlich, Konstantinos Ioannidis, Makram Nasar, Ismaeel Abu Alkian, Yuval Daskal, Nofar Atari, Limor Kliker, Nir Rainy, Matan Hofree, Sigal Shafran Tikva, Inbal Houri, Arrigo Cicero, Chiara Pavanello, Cesare R. Sirtori, Jordana B. Cohen, Julio A. Chirinos, Lisa Deutsch, Merav Cohen, Amichai Gottlieb, Adina Bar-ChaimOren Shibolet, Michal Mandelboim, Shlomo L. Maayan, Yaakov Nahmias^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart themetabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran’s Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARP-dependent mechanism in both alpha and delta variants. Analysis of 3,233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lowermarkers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A 9 subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARPPPshould be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical 60 trial number: NCT04661930.

Original language	American English
Article number	e79946
Journal	eLife
Volume	12
DOIs	https://doi.org/10.7554/eLife.79946
State	Published - Jan 2023
Externally published	Yes

Bibliographical note

Funding Information:
Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. The authors would like to thank Prof. Benjamin R. tenOever and his team at the Icahn School of Medicine for providing viral load quantifications (Figure 3D) and fixed drug-treated SARS-CoV-2 infected primary cell cultures at their BSL3 facility at the request of the study authors. ??????????????????????

Funding Information:
Statistical analysis of the Israeli studies was done by BioStats Statistical Consulting Ltd. (Maccabim, Israel), funded by the sponsor. Data management is performed in compliance with GCP and 21 CFR part 1. Statistical analyses and reporting are performed in compliance with E6 GCP, E9, and ISO 14155. Independently validated by the author. Statistical analysis of the Italian study was done by Prof. Arrigo Cicero and Dr. Chiara Pavanello. Statistical analysis of the US study was done by Prof. Jordana Cohen.

Funding Information:
demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical trial number: NCT04661930.

Publisher Copyright:
© 2023, eLife Sciences Publications Ltd. All rights reserved.

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Ehrlich, A., Ioannidis, K., Nasar, M., Alkian, I. A., Daskal, Y., Atari, N., Kliker, L., Rainy, N., Hofree, M., Tikva, S. S., Houri, I., Cicero, A., Pavanello, C., Sirtori, C. R., Cohen, J. B., Chirinos, J. A., Deutsch, L., Cohen, M., Gottlieb, A., ... Nahmias, Y. (2023). Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, Observational, and Non-Randomized Open Label Interventional Study. eLife, 12, Article e79946. https://doi.org/10.7554/eLife.79946

@article{e09a306ee63a4b5fb35c2a5a77171caa,

title = "Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, Observational, and Non-Randomized Open Label Interventional Study",

abstract = "Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart themetabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran{\textquoteright}s Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARP-dependent mechanism in both alpha and delta variants. Analysis of 3,233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lowermarkers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A 9 subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARPPPshould be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical 60 trial number: NCT04661930.",

author = "Avner Ehrlich and Konstantinos Ioannidis and Makram Nasar and Alkian, {Ismaeel Abu} and Yuval Daskal and Nofar Atari and Limor Kliker and Nir Rainy and Matan Hofree and Tikva, {Sigal Shafran} and Inbal Houri and Arrigo Cicero and Chiara Pavanello and Sirtori, {Cesare R.} and Cohen, {Jordana B.} and Chirinos, {Julio A.} and Lisa Deutsch and Merav Cohen and Amichai Gottlieb and Adina Bar-Chaim and Oren Shibolet and Michal Mandelboim and Maayan, {Shlomo L.} and Yaakov Nahmias",

note = "Funding Information: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. The authors would like to thank Prof. Benjamin R. tenOever and his team at the Icahn School of Medicine for providing viral load quantifications (Figure 3D) and fixed drug-treated SARS-CoV-2 infected primary cell cultures at their BSL3 facility at the request of the study authors. ?????????????????????? Funding Information: Statistical analysis of the Israeli studies was done by BioStats Statistical Consulting Ltd. (Maccabim, Israel), funded by the sponsor. Data management is performed in compliance with GCP and 21 CFR part 1. Statistical analyses and reporting are performed in compliance with E6 GCP, E9, and ISO 14155. Independently validated by the author. Statistical analysis of the Italian study was done by Prof. Arrigo Cicero and Dr. Chiara Pavanello. Statistical analysis of the US study was done by Prof. Jordana Cohen. Funding Information: demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical trial number: NCT04661930. Publisher Copyright: {\textcopyright} 2023, eLife Sciences Publications Ltd. All rights reserved.",

year = "2023",

month = jan,

doi = "10.7554/eLife.79946",

language = "American English",

volume = "12",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

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Ehrlich, A, Ioannidis, K, Nasar, M, Alkian, IA, Daskal, Y, Atari, N, Kliker, L, Rainy, N, Hofree, M, Tikva, SS, Houri, I, Cicero, A, Pavanello, C, Sirtori, CR, Cohen, JB, Chirinos, JA, Deutsch, L, Cohen, M, Gottlieb, A, Bar-Chaim, A, Shibolet, O, Mandelboim, M, Maayan, SL & Nahmias, Y 2023, 'Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, Observational, and Non-Randomized Open Label Interventional Study', eLife, vol. 12, e79946. https://doi.org/10.7554/eLife.79946

TY - JOUR

T1 - Efficacy and safety of metabolic interventions for the treatment of severe COVID-19

T2 - in vitro, Observational, and Non-Randomized Open Label Interventional Study

AU - Ehrlich, Avner

AU - Ioannidis, Konstantinos

AU - Nasar, Makram

AU - Alkian, Ismaeel Abu

AU - Daskal, Yuval

AU - Atari, Nofar

AU - Kliker, Limor

AU - Rainy, Nir

AU - Hofree, Matan

AU - Tikva, Sigal Shafran

AU - Houri, Inbal

AU - Cicero, Arrigo

AU - Pavanello, Chiara

AU - Sirtori, Cesare R.

AU - Cohen, Jordana B.

AU - Chirinos, Julio A.

AU - Deutsch, Lisa

AU - Cohen, Merav

AU - Gottlieb, Amichai

AU - Bar-Chaim, Adina

AU - Shibolet, Oren

AU - Mandelboim, Michal

AU - Maayan, Shlomo L.

AU - Nahmias, Yaakov

N1 - Funding Information: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. The authors would like to thank Prof. Benjamin R. tenOever and his team at the Icahn School of Medicine for providing viral load quantifications (Figure 3D) and fixed drug-treated SARS-CoV-2 infected primary cell cultures at their BSL3 facility at the request of the study authors. ?????????????????????? Funding Information: Statistical analysis of the Israeli studies was done by BioStats Statistical Consulting Ltd. (Maccabim, Israel), funded by the sponsor. Data management is performed in compliance with GCP and 21 CFR part 1. Statistical analyses and reporting are performed in compliance with E6 GCP, E9, and ISO 14155. Independently validated by the author. Statistical analysis of the Italian study was done by Prof. Arrigo Cicero and Dr. Chiara Pavanello. Statistical analysis of the US study was done by Prof. Jordana Cohen. Funding Information: demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical trial number: NCT04661930. Publisher Copyright: © 2023, eLife Sciences Publications Ltd. All rights reserved.

PY - 2023/1

Y1 - 2023/1

N2 - Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart themetabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran’s Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARP-dependent mechanism in both alpha and delta variants. Analysis of 3,233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lowermarkers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A 9 subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARPPPshould be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical 60 trial number: NCT04661930.

AB - Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart themetabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran’s Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARP-dependent mechanism in both alpha and delta variants. Analysis of 3,233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lowermarkers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A 9 subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARPPPshould be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical 60 trial number: NCT04661930.

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U2 - 10.7554/eLife.79946

DO - 10.7554/eLife.79946

M3 - Article

C2 - 36705566

AN - SCOPUS:85148210123

SN - 2050-084X

VL - 12

JO - eLife

JF - eLife

M1 - e79946

ER -

Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, Observational, and Non-Randomized Open Label Interventional Study

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